NMDA receptors are unique from other glutamate receptors in that they are permeable to calcium. This calcium permeability is necessary for neuronal long-term potentiation, the cellular basis of learning and memory, and can also cause excitotoxicity and cell death in disease conditions like stroke and epilepsy. Therefore understanding mechanisms that influence gating and permeability of NMDA receptors will provide more insight into the processes that control plasticity and excitotoxicity. The gating and permeability of NMDA receptors are influenced by a variety of extracellular and intracellular signals, including protein kinase A (PKA), which is the focus of this application. PKA has been shown to increase both the amplitude and calcium component of NMDA currents, which then influences many types of neuronal signaling, including long-term potentiation. The mechanism by which PKA modulates NMDA receptors, however, is completely unknown. In this application, therefore, modulation of NMDA receptors will be investigated using two aims. The goal of the first aim is to determine the mechanism by which NMDA receptor gating and permeability are modulated by PKA using single NMDA receptor recordings, pharmacological manipulations, kinetic modeling, and site- directed mutagenesis. In the second aim, the effect of PKA modulation on synaptic transmission, calcium influx, and long-term potentiation will be investigated. The results of these experiments will therefore determine the mechanism by which PKA alters NMDA receptor gating and give insight as to how this modulation may ultimately change neuronal output. PUBLIC HEALTH RELEVANCE: Calcium influx into neurons through NMDA receptors causes a variety of effects, including neuronal plasticity, the cellular basis of learning, as well as cel death in conditions like epilepsy and stroke. This application will investigate one mechanism by which NMDA receptor activity, particularly calcium influx, is regulated by a kinase pathway. Understanding the mechanisms by which NMDA gating and calcium influx is modulated will therefore give more insight into the mechanisms of learning and memory, as well as potential methods to prevent cell death in various disease states.